Chronic activation of p38α in skeletal muscle causes necrotic changes, but also abolishes expression of MK2, MK3, and MKK6 and the muscle recovers.

The MAPK p38α is associated with skeletal muscle's development, differentiation and functionality. But, as it is overactive in muscle diseases and aging, it was proposed to be a pivotal promoter of these processes as well. It is not clear how p38α is involved in these disparate activities, in particular whether its chronic activation alone is sufficient to cause them. We established a mouse model designed to study the effects of p38α per se in skeletal muscle. p38α activation is achieved by inducible expression, in muscle, of an intrinsically active variant, p38α(D176A+F327S). Two weeks following expression muscle degeneration and necrotic changes were observed, accompanied with elevation of p53, caspase 3, and γH2AX; and, intriguingly, suppression of the p38's substrates MK2 and MK3 and its activator MKK6. At later timepoints the tissue recovered, apoptotic markers disappeared, but MK2, MK3, and MKK6 remained suppressed, perhaps as a response that restrains p38α-mediated damage and allows recovery. Induction of p38α(D176A+F327S) in young mice (2 months old) caused milder effects, but MK2, MK3, and MKK6 were suppressed. The p38α(D176A+F327S) effects were associated with altered level of ∼2000 mRNA molecules. For 1700 genes, the effect was transient and for ∼300 constant. Stress-induced activation of p38α in C2C12 myoblasts was also associated with MK2 downregulation, but with constant elevation of apoptotic markers. Thus, chronic activation of p38α per se in skeletal muscle is sufficient to cause damage reminiscent of aging effects, but cannot impose full-scale and lasting aging phenotype. The tissue recovers while suppressing the p38α pathway.